Inflammatory bowel disease (IBD) patients have an increased risk of developing a colorectal malignancy that continues to increase with the duration of the disease. Unlike cancers that develop in non-IBD patients, those developing in the setting of IBD are very difficult to detect at an early, potentially curable stage. Additionally, precancerous dysplasia is histologically difficult to distinguish from the regenerative and inflammatory changes characteristically present in the colonic mucosa of the IBD patient. As a result, our overall goals are to identify clinically useful, objective markers of increased cancer risk that are independent of the endoscopist's ability to identify a visible lesion, and which do not rely solely on histologic examination of biopsy materials. It has recently been shown that the regenerative mucosa of some patients with long-standing IBD (greater than 7 years) demonstrate microsatellite instability, a molecular alteration which may result from defects in the fidelity of DNA nuclear repair mechanisms in the colonic epithelium. These DNA repair defects could lead to the development of genetic instability, and could predispose large areas of the colonic mucosa to the acquisition of mutations or other abnormalities in genes known to be involved in the genesis of colon cancer. This project investigates the role of microsatellite instability and defective DNA mismatch repair in the development of dysplasia and carcinoma in formalin-fixed, paraffin- embedded archival tissues from IBD patients. Experiments in this project will employ microdissection and standard molecular biologic techniques to address the following hypotheses: 1) that the microsatellite instability observed in the colonic mucosa of IBD patients occurs within epithelial cells, and not within stromal or inflammatory cells within the lamina propria; 2) that microsatellite instability is associated with a specific germline alteration in the hMSH2 gene in patients with IBD, and that the hMSH2 alteration [occurs with increased frequency in patients with high grade dysplasia or carcinoma], and 3) that mutations in the exonic repeat sequences of the transforming growth factor beta receptor II (TGFbeta RII), Insulin-like growth factor II receptor (IGFR), and BAX genes occur early in the neoplastic progression of patients with IBD, and that they occur in association with microsatellite instability and the altered hMSH2 genotype.